The Endocannabinoid System:  


The endocannabinoid system consists of an internal network of cannabinoid receptors (CBRs), located throughout the nervous system: CNS (brain and spinal cord) and PNS (peripheral nervous system = nerves that branch out from the brain and spinal cord and extend to other parts of the body including muscles and organs) as well as upon certain immune cells. Due to the location of their receptors, the endocannabinoid system, therefore, has a direct effect upon the nervous and immune systems.  

A type of fat-soluble neurotransmitter, known as an endocannabinoid (endogenous cannabinoid), as the name suggests, is produced endogenously (by our body) and has been shown to bind to these cannabinoid receptors (CBRs), upon binding they then can influence many bodily systems.  


Functions of the Endocannabinoid System: 

The endocannabinoid system is involved in maintaining homeostasis by regulating the following internal physiological processes:  







Inflammation and pain  

Fertility and pregnancy  


There are currently two types of CBRs that have been discovered:  


CB1 - abundant in CNS (hippocampus and amygdala) 

CB2 - abundant in PNS and upon immune cells 



(a type of neurotransmitter produced within the body) 


2-arachidonoylglyerol (2-AG) - binds to both CBRs but most abundantly to CB1 in the CNS 

anandamide (AEA) - binds to both CBRs but most abundantly to CB2 in the PNS and upon immune cells.  


*Endocannabinoids are produced as and when the body needs them and therefore their levels will fluctuate as the body constantly responds to its internal and external environments to maintain homeostasis.   


Endocannabinoid Enzymes:  

Enzymes are biological molecules (proteins) that govern human physiology by acting as mediators for chemical reactions that take place within every cell.   


After endocannabinoids have carried out their function – they are broken down by specific enzymes. There are two enzymes responsible for breaking down endocannabinoids:  


Fatty acid amide hydrolase (FAAH) - which breaks down AEA  

Monoacylglycerol acid lipase (MAG lipase) - which breaks down 2-AG 


The endocannabinoid system is made up of: 

(discovered in the early 1990s)


Cannabinoid receptors (CB1 and CB2)  

Endocannabinoids (2-AG and AEA) 

Enzymes (FAAH and MAG lipase)  


The discovery of the endocannabinoid system was made due to the study of THC, a type of psychoactive exogenous cannabinoid, found in marijuana, that produces the well-known ‘high’ upon inhalation (smoking).  

Hemp contains another exogenous cannabinoid, known as Cannabidiol (CBD), however, this cannabinoid is nonpsychoactive (unlike THC).  


Both THC and CBD are exogenous cannabinoids (produced and obtained from outside the body) and originate from the Cannabis plant, however, THC comes from marijuana, which has been grown from seeds that have a high THC content whereas, CBD comes from Hemp, which has been grown from seeds that have a high CBD content and low THC content (0.3%).  


CBD and THC have the same molecular structure:  


21 carbon atoms 

30 hydrogen atoms 

2 oxygen atoms.  


However, they have been shown to act very differently within the human body due to slight differences in how their atoms are arranged.  


Both CBD and THC have a similar molecular structure to our own endocannabinoids (2-AG and AEA) and therefore, they have both been shown to interact with our cannabinoid receptors (CBRs) located throughout our endocannabinoid system.  



The pharmacodynamics of THC and CBD (their specific mechanism of action within the human body) is not yet fully understood. However, evidence suggests that their effects are mediated through the following ways:   


THC has been shown to bind to CB1 receptors (weak agonist) in the brain and produces the ‘high’ associated with its use, which also includes increased appetite, reduced pain, and emotional and cognitive changes. 


CBD has been shown to act as a negative allosteric modulator of CB1 receptors, which means it decreases the efficacy of CB1 receptors.   


Further evidence suggests that CBD has the following modes of action:  


Activates serotonin receptors (5-HT1A/2A/3A receptors) 

Activates receptors involved in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, pain, and inflammation (TRPV1–2 vanilloid receptors).  

CBD stimulates the activity of glycine-receptors, which are involved in inhibitory neurotransmission.   

alpha-1 adrenergic receptors are involved in our fight and flight response, CBD has been shown to act as an alpha-1 adrenergic receptor antagonist, which means it inhibits the function of this receptor and therefore plays an important role blood pressure regulation.     

CBD has been shown to interact with opioid receptors, further modulating pain perception.  

CBD inhibits the reuptake of neurotransmitters; noradrenaline, dopamine, serotonin and GABA, as well as of cannabinoid; anandamide (AEA) - potentiating their effects.  

CBD has been shown to act on mitochondria Ca2+ stores, this provides a protective mechanism against mitochondria dysfunction.  

CBD blocks low-voltage-activated (T-type) Ca2+ channels (involved in neurotransmission), preventing excessive excitatory neurotransmission, and is therefore neuroprotective. 

CBD inhibits the activity of fatty amide hydrolase (FAAH), one of the enzymes responsible for breaking down endocannabinoids.  

Evidence suggests that CBD may bind to a receptor that hasn’t been discovered yet. 



The pharmacokinetics of CBD refers to the movement of CBD into the body, through the body, and out of the body.  


Bioavailability is a term used to describe how much of a substance enters the blood circulation after administration. This gives us an indication of how well/ poor a substance can be absorbed by the body and how much if then left to have an active effect. The bioavailability of a substance will be different depending on how it is administered.  


CBD administration and bioavailability:  


After inhalation, the bioavailability of CBD is 11% to 45%. Absorbed via the lungs straight into the bloodstream. Effects are felt within 10 minutes.  


After sublingual administration, the bioavailability of CBD is 13% - 19%. Absorbed under the tongue via the sublingual gland straight into the bloodstream. Effects are felt within 20 minutes. 


After oral administration, the bioavailability of CBD is approximately 6% - 20%. Absorbed via the digestive tract and passes through the liver before reaching the bloodstream. Effects are felt between 30 – 120 minutes.   


The elimination half-life of CBD is 18–32 hours. This means it takes between 18-32 hours for the body to eliminate CBD from the bloodstream by half (50%) its initial dose.  


CBD is metabolized by liver enzymes (CYP2C19 and CYP3A4), and by intestinal enzymes (UGT1A7, UGT1A9, and UGT2B7). This is why oral administration of CBD, which passes through the digestive tract and liver, is the least effective (low bioavailability), as a lot of CBD will be broken down by these enzymes before reaching the bloodstream.   


With topical administration, CBD only interacts with local endocannabinoid receptors within the skin (does not enter the bloodstream) and is therefore useful for localised pain such as arthritic joints or sore muscles. 


CBD and PNI (Psycho-Neuro-Immunology): 


CBD is effective at reducing stress which suggests that it may have a positive influence on the HPA-axis. CBD also acts as an alpha-1 adrenergic receptor antagonist, and therefore reduces sympathetic nervous system dominance (fight and flight) - the release of adrenaline and noradrenaline, which stimulates the production of cytokines and subsequent inflammation. CBD acts directly upon immune cells, reducing cytokine production, which in turn reduces systemic and neuro-inflammation. CBD plays a role in Ca2+ homeostasis, preventing excessive excitatory neurotransmission, and is therefore neuroprotective. Due to the specific pharmacodynamic (mode of action) of CBD, it is clear that CBD directly influences PNI (psycho-neuro-immunology) and can, therefore, be useful at mitigating the symptoms are associated with PNI dysregulation.